Formoterol which is the compound N-[2-hydroxy-5-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl) amino)ethyl) phenyl] formamide, is known from U.S. Pat. No. 3,994,974. It is known to be a bronchodilator and used in the treatment of inflammatory or obstructive airways diseases.
GB 247680 discloses pregna-1,4-diene-3,20-dione-16-17-acetal-21 esters and their use in the treatment of inflammatory conditions. The compounds have the general structure:
wherein R1 is 2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and R2 is acetyl or isobutanoyl. Ciclesonide is the INN for a compound of formula I in which R1 is cyclohexyl and R2 is isobutanoyl with the chemical name [11β,16α(R)]-16,17-[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-dien-3,20-dion.
This compound has undergone evaluation as an antiasthmatic and pharmacokinetic studies show that it will be useful in an inhaler formulation. Ciclesonide is only moderately absorbed after oral administration and has low systemic activity. Concentration of the drug in the lungs is high and metabolism by liver oxidases is very high, giving the drug a low plasma half-life. Systemic activity of ciclesonide is three times lower than that of budesonide, but anti-inflammatory activity is higher for the former.
DE 19541689 is related to the combined use of ciclesonide with a β-sympathomimetic, for the treatment of disorders of the respiratory tract. As an example a metered dose aerosol composition comprising ciclesonide and formoterol in tricholorofluoromethane (R11) as propellant is disclosed.
EP-A-0504112 discloses examples of pharmaceutical compositions for aerosol use comprising formoterol fumarate.
WO 93/11747 discloses a pharmaceutical suspension formulation suitable for aerosol administration, consisting essentially of a therapeutically effective amount of a drug and a propellant selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof, the formulation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug. The application specifically discloses formulations of formoterol fumarate in HFA 134a, HFA 227 and 1:1 mixtures of HFA 134a and HFA 227.
WO 93/11745 discloses pharmaceutical aerosol formulations, substantially free of surfactant containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants and up to 5% of a polar co-solvent. Preferred propellants are HFA 134a and HFA 227, which are preferably used alone. The preferred polar co-solvent is ethanol and it is stated that in general only small quantities e.g. 0.05 to 3.0% w/w of polar co-solvent are required to improve the dispersion and the use of quantities in excess of 5% w/w may dis-advantageously tend to dissolve the medicament.
WO 97/47286 discloses a pharmaceutical suspension formulation suitable for aerosol administration, consisting essentially of: (a) from 0.0025 to 0.1% w/v of micronized formoterol, or an acid addition salt thereof and (b) from 0.1 to 5.0% w/v ethanol, (c) HFA 134a, HFA 227 or a mixture of HFA 227 and HFA 134a and optionally (d) a surfactant other than a monoacetylated or diacetylated monoglyceride, the formulation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug. The application specifically discloses formulations comprising formoterol fumarate dispersed in HFA 134a, HFA 227 or mixtures thereof and 1 to 3% ethanol. It is stated that it is important to ensure the formoterol fumarate does not come into contact with high concentrations e.g. above 10% w/w, of ethanol since the drug would dissolve leading to instability and crystal growth problems in the final formulation and that the maximum concentration of ethanol during formulation is preferably less than 5%. It is stated that aerosol compositions consisting of formoterol fumarate, HFA 134a and ethanol have proved to be extremely sensitive to ethanol concentration and an ethanol concentration of 3.5% w/w may cause unacceptable crystal growth.
WO 98/52542 discloses a pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formula (I):
wherein R1 is 2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and R2 is acetyl or isobutanoyl and a hydrofluorocarbon propellant, preferably selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof, and cosolvent, preferably ethanol, in an amount effective to solubilize the compound of formula (I) and optionally a surfactant. The application specifically discloses solution formulations comprising ciclesonide (1 to 5 mg/ml) in HFA 134a, HFA 227 or mixtures of HFA 134a and HFA 227 and 5 to 20% by weight ethanol.
Despite the various approaches used in formulating drugs for use in aerosol inhalation, a number of serious difficulties and uncertainties are still often encountered in attempting to develop a physically and chemically stable HFA 134a and/or HFA 227 based formulation that reliably delivers an accurate dose of drug having the proper particle size range. In particular formoterol is reported to be very sensitive in HFA 134a and/or HFA 227 propellant. Up to date no medicinal aerosol formoterol product based on HFA technology is available on the market.